Sodium acetate (SA), is approved by European food control authorities, and is an edible salt that is added to food as a seasoning. It has a wide range of applications. Firstly, it is used as antibacterial additive and preservative in food compounds; it is an inhibitor of gram-negative bacteria, and fungi that grow in food. Secondly, oysters shelf life can be extend through dipping in sodium acetate. Sodium acetate is generally prepared by mixing an aqueous solution of sodium carbonate or hydroxide with an aqueous solution of acetic acid. The recovery of sodium acetate, in this aqueous solution, is generally either by crystallization or evaporation using techniques such as spray drying (U.S. Pat. No. 2,895,990). Beside its widespread use in food industry, up-to-day, little is known about the coating property of sodium acetate for pharmaceutical nano-formulations.
Chitosan is a polysaccharide obtained from the deacetylation of chitin and have been used as a nanocarrier for novel drug delivery system because of its biodegradable and biocompatible properties (H. Zheng, et al., Pharm Res. 32:2038-2050 (2015)). Among chitosan based nanocarriers, chitosan crosslinked with polyanion triphosphate (TPP) based nanoparticles (NPs) have been widely used for the nano-encapsulation of HIV/AIDS microbicide such as tenofovir (TFV). The solubility in water, log P and and its oral bioavailability of TFV are 13.4 mg/mL, −1.1, and, 25-39%, respectively. TFV is a BCS class III drug (A. A. Dateand, et al., Biomaterials. 34:6202-6228 (2013)).
However, the nano-encapsulation process using chitosan-TPP ionic gelation, and a water soluble drug such as TFV, has several limitations. Firstly, the encapsulation efficiency (EE %) of a water soluble drug, such as TFV is typically very low. For instance, Meng, et al. encapsulated only 5.83% of TFV in chitosan NPs. Secondly, chitosan NPs exhibits an initial burst release leading to a failure to sustain release, and protect drugs. Thirdly, the freeze drying process is not effective for chitosan based NPs in absence of cryoprotectant. This leads to the aggregation of NPs.
Therefore, there is a need to develop a new and modified in situ formation of sodium acetate, which can be used to uniformly coat pharmaceutically loaded NPs (such as chitosan NPs) and dramatically increase the physicochemical properties of the NPs (e.g. improvement of the freeze drying process, EE %, non-aggregation of NPs without the use of cryoprotectant, physical stability, and sustained drug release profile).
This invention provides a series of sodium-acetate-coated pharmaceutically-loaded NPs. This invention further provides a new and improved in situ formation of sodium acetate, which can be used to uniformly coat pharmaceutically loaded NPs (such as chitosan NPs) and dramatically increase the physicochemical properties of the NPs.
According to one embodiment of the invention, the inventive method comprises the steps of i) generating in situ sodium acetate from half neutralization of acetic acid with sodium hydroxide, and ii) coating pharmaceutically loaded NPs during freeze-drying process.
Corresponding reference numerals indicate corresponding parts throughout the several views of drawings.